This R01 renewal dissects the role and action of a fungal product that inactivates innate immunity. Even in healthy hosts, the systemic mycoses produce immune disturbances and progressive disease. This finding implies that the fungi disable immune responses, but little is known about the molecular bases. This knowledge gap limits development of new therapies. We've developed Blastomyces dermatitidis and murine infection into an excellent model to unravel such enigmas. We have reported that CCR2+ inflammatory monocytes promote fungal vaccine immunity, yet host mediators retard their influx into the lung upon vaccination at this site. We focus here on a yeast product that undercuts these cells and innate immunity, facilitating progressive infection. We propose that dipeptidyl peptitidase IVA (DPP4A) blunts innate lung immunity. DPP4A is an oligopepti- dase that cleaves protein after a 2-position proline at the N-terminus. Mammalian DPP4 (CD26) inactivates cytokine/chemokine, tempering immunity. While such activity is unreported in microbes, DPP4 is conserved in bacteria, parasites and fungi, and DPP4 inhibitors are being used to treat diabetes, heart disease & Alzheimer's. We have preliminary data that fungal DPP4A blunts innate immunity and that silencing or deleting DPP4A attenuates B. dermatitidis in a GM-CSF & CCR2 dependent manner. We hypothesize that DPP4A inactivates GM-CSF & CCL2 (recruits CCR2+ cells) and digests the lung extracellular matrix that displays chemokine, and that these events blunt influx/function of CCR2+ monocytes, macrophages and neutrophils. We aim to: 1. Define DPP4A action on GM-CSF and its effect on macrophages and neutrophils. Fungal DPP4A will be studied for action on GM-CSF and inactivation of the cytokine. Mice infected with DPP4A-plus or -minus yeast will be used to study whether & how DPP4A-clipped GM-CSF disables leukocytes and assess drug inhibitor or cytokine therapy. 2. Delineate DPP4A action on CCL2 and the impact on CCR2+ inflammatory monocytes. Fungal DPP4A will be studied for inactivation of C-C chemokine, and the ensuing impact on CCR2+ monocyte recruitment and function to define the mechanics that underpin failed influx and function of the cells during innate resistance to fungal infection. 3. Analyze DPP4A action on cell matrix and the impact on CCR2+ cell migration. Fungal DPP4A will be studied for action on collagen I & the glycosaminoglycan heparin, ECM elements that display chemokine to leukocytes. CCR2+ GFP reporter mice/cells will be used to assay how DPP4A action on ECM alters cell migration in vitro and in vivo. Our work tackles a prevailing knowledge gap: the basis for disease progression during systemic mycosis. It breaks new ground by exposing yeast mimicry of a host tactic that tempers innate immunity by regulating 2 key mediators: GM-CSF & CCR2+ cells. The actions can be targeted with drug inhibitors or immune therapy.